1. Field of the Invention
This invention is directed to novel polyhydroxy derivatives of glycopeptide antibiotics and related compounds. This invention is also directed to pharmaceutical compositions containing such polyhydroxy glycopeptide derivatives, methods of using such polyhydroxy glycopeptide derivatives as antibacterial agents, and processes and intermediates useful for preparing such polyhydroxy glycopeptide derivatives.
2. Background
Glycopeptides (e.g. dalbaheptides) are a well-known class of antibiotics produced by various microorganisms (see Glycopeptide Antibiotics, edited by R. Nagarajan, Marcel Dekker, Inc. New York (1994)). These complex multi-ring peptide compounds are very effective antibacterial agents against a majority of Gram-positive bacteria. Although potent antibacterial agents, the glycopeptides antibiotics are not used in the treatment of bacterial diseases as often as other classes of antibiotics, such as the semi-synthetic penicillins, cephalosporins and lincomycins, due to concerns regarding toxicity.
In recent years, however, bacterial resistance to many of the commonly-used antibiotics has developed (see J. E. Geraci et al., Mayo Clin. Proc. 1983, 58, 88-91; and M. Foldes, J. Antimicrob. Chemother. 1983, 11, 21-26). Since glycopeptide antibiotics are often effective against these resistant strains of bacteria, glycopeptides such as vancomycin have become the drugs of last resort for treating infections caused by these organisms. Recently, however, resistance to vancomycin has appeared in various microorganisms, such as vancomycin-resistant enterococci (VRE), leading to increasing concerns about the ability to effectively treat bacterial infections in the future (see Hospital Infection Control Practices Advisory Committee, Infection Control Hospital Epidemiology, 1995, 17, 364-369; A. P. Johnson et al., Clinical Microbiology Rev., 1990, 3, 280-291; G. M. Eliopoulos, European J Clinical Microbiol., Infection Disease, 1993, 12, 409-412; and P. Courvalin, Antimicrob. Agents Chemother, 1990, 34, 2291-2296).
A number of derivatives of vancomycin and other glycopeptides are known in the art. For example, see U.S. Pat. Nos. 4,639,433; 4,643,987; 4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889. Other derivatives are disclosed in EP 0 802 199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO 98/52589; WO 98/52592; and in J. Amer. Chem. Soc., 1996, 118, 13107-13108; J. Amer. Chem. Soc., 1997, 119, 12041-12047; and J. Amer. Chem. Soc., 1994, 116, 4573-4590.
Despite the above referenced disclosures, a need currently exists for novel glycopeptide derivatives having effective antibacterial activity and an improved mammalian safety profile. In particular, a need exists for glycopeptide derivatives which are effective against a wide spectrum of pathogenic microorganisms, including vancomycin-resistant microorganisms, and which have reduced tissue accumulation and/or nephrotoxicity.
The present invention provides novel polyhydroxy glycopeptide derivatives having highly effective antibacterial activity and an improved mammalian safety profile. More specifically, the polyhydroxy glycopeptide derivatives of the invention unexpectedly exhibit reduced tissue accumulation and/or nephrotoxicity when administered to a mammal.
Accordingly, the invention provides a compound of the invention, which is a glycopeptide of formula I: 
wherein:
R1 is an amino containing saccharide group substituted on the amine with a substituent that comprises two or more (e.g. 2, 3, 4, 5, or 6) hydroxy (OH) groups;
R2 is hydrogen or a saccharide group optionally substituted with xe2x80x94Raxe2x80x94Yxe2x80x94Rb(Z)x, Rf, xe2x80x94C(O)Rf, xe2x80x94C(O)Rf, or xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R3 is xe2x80x94ORc, xe2x80x94NRcRc, xe2x80x94Oxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, xe2x80x94NRcxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, xe2x80x94NRCRe, or xe2x80x94Oxe2x80x94Re;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, xe2x80x94C(O)Rd and a saccharide group optionally substituted with xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, Rf, xe2x80x94C(O)Rf, or xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R5 is selected from the group consisting of hydrogen, halo, xe2x80x94CH(Rc)xe2x80x94NRcRc, xe2x80x94CH(Rc)xe2x80x94NRcRc, xe2x80x94CH(Rc)xe2x80x94NRcxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x,xe2x80x94CH(Rc)xe2x80x94Rx, and xe2x80x94CH(Rc)xe2x80x94NRcxe2x80x94Raxe2x80x94C(xe2x95x90O)xe2x80x94Rx;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, xe2x80x94C(O)Rd and a saccharide group optionally substituted with xe2x80x94NRcxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, or R5 and R6 can be joined, together with the atoms to which they are attached, form a heterocyclic ring optionally substituted with xe2x80x94NRcxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x;
R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, and xe2x80x94C(O)Rd;
R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
R10 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; or R8 and R10 are joined to form xe2x80x94Ar1xe2x80x94Oxe2x80x94Ar2xe2x80x94, where Ar1 and Ar2 are independently arylene or heteroarylene;
R11 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic, or R10 and R11 are joined, together with the carbon and nitrogen atoms to which they are attached, to form a heterocyclic ring;
R12 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, xe2x80x94C(O)Rd, xe2x80x94C(NH)Rd, xe2x80x94C(O)NRcRc, xe2x80x94C(O)ORd, xe2x80x94C(NH)NRcRc and xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, or R11 and R12 are joined, together with the nitrogen atom to which they are attached, to form a heterocyclic ring;
R13 is selected from the group consisting of hydrogen or xe2x80x94OR14;
R14 is selected from hydrogen, xe2x80x94C(O)Rd and a saccharide group;
each Ra is independently selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene;
each Rb is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene and substituted alkynylene, provided Rb is not a covalent bond when Z is hydrogen;
each Rc is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic and xe2x80x94C(O)Rd;
each Rd is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
Re is a saccharide group;
each Rf is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic;
Rx is a nitrogen-linked amino saccharide or a nitrogen-linked heterocycle;
X1, X2 and X3 are independently selected from hydrogen or chloro;
each Y is independently selected from the group consisting of oxygen, sulfur, xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94NRcxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRcC(O)xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NRcSO2xe2x80x94, xe2x80x94C(O)NRcxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94SO2NRcxe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94P(O)(ORc)Oxe2x80x94, xe2x80x94P(O)(ORc)NRcxe2x80x94, xe2x80x94OP(O)(ORc)Oxe2x80x94,xe2x80x94OP(O)(ORc)NRcxe2x80x94, xe2x80x94OC(O)Oxe2x80x94, xe2x80x94NRcC(O)Oxe2x80x94, xe2x80x94NRcC(O)NRcxe2x80x94, xe2x80x94OC(O)NRcxe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, and xe2x80x94NRcSO2NRcxe2x80x94;
each Z is independently selected from hydrogen, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;
n is 0, 1 or 2; and
x is 1 or2;
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof;
Preferably, R1 is an amino containing saccharide group substituted on the amine with a group comprising two or more (e.g. 2, 3, 4, 5, or 6) hydroxy groups that is selected from xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, Rf, xe2x80x94C(O)Rf, and xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z). For example, R1 is preferably a saccharide group of the formula: 
wherein R15 comprises two or more (e.g. 2, 3, 4, 5, or 6) hydroxy groups and is selected from xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, Rf, xe2x80x94C(O)Rf, and xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x; and R16 is hydrogen or methyl. In one preferred embodiment R15 is substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, substituted alkyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, substituted alkynyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, substituted cycloalkenyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94, or heterocyclic-C(O)xe2x80x94; wherein R15 comprises two or more hydroxy groups. More preferably, R15 is substituted alkyl, substituted alkenyl, substituted alkynyl, substituted alkyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, substituted alkynyl-C(O)xe2x80x94; wherein R15 comprises two or more hydroxy groups.
In another preferred embodiment R15 is a group of formula xe2x80x94CH2xe2x80x94CH(OH)CH(OH)CH2xe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, or xe2x80x94CH2xe2x80x94CH(OH)CH(OH)CH2xe2x80x94R17 wherein Y, Rb, Z and x have any of the values or preferred values described herein, and R17 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic.
Preferably, R2 is hydrogen.
Preferably, R3 is xe2x80x94ORc or xe2x80x94NRcRc; more preferably R3 is xe2x80x94OH.
Particularly preferred R3 groups include xe2x80x94OH; xe2x80x94NHxe2x80x94(CH2)3xe2x80x94N(CH3)2N-(Dxe2x80x94glucosamine); xe2x80x94NHCH(CO2CH3)CH2CO2CH3; xe2x80x94NH(CH2)3-(morpholin-4-yl); xe2x80x94NH(CH2)3xe2x80x94NH(CH2)2CH3; xe2x80x94NH(CH2-piperidin-1-yl; xe2x80x94NH(CH2)4NHC(N)NH2; xe2x80x94NH(CH2)2-N+(CH3)3; xe2x80x94NHCH(COOH)(CH2)3NHC(N)NH2; xe2x80x94NHxe2x80x94[(CH2)3xe2x80x94NHxe2x80x94]3xe2x80x94H; xe2x80x94N[(CH2)3N(CH3)2]2; xe2x80x94NH(CH2)3-imidazol-1-yl; xe2x80x94NHCH2-4-pyridyl; xe2x80x94NH(CH2)3CH3; xe2x80x94NH(CH2)2OH; xe2x80x94NH(CH2)5OH; xe2x80x94NH(CH2)2OCH3; xe2x80x94NHCH2-tetrahydrofuran-2-yl; xe2x80x94N[(CH2)2OH]2; xe2x80x94NH(CH2)2N[(CH2)2OH]2; xe2x80x94NHCH2COOH; xe2x80x94NHCH(COOH)CH2OH; xe2x80x94NH(CH2)2COOH; N-(glucamine); xe2x80x94NH(CH2)2COOH; xe2x80x94NH(CH2)3SO3H; xe2x80x94NHCH(COOH)(CH2)2NH2; xe2x80x94NHCH(COOH)(CH2)3NH2; xe2x80x94NHCH(COOH)CH2CO2(CH2)3-N+(CH3)3; xe2x80x94NHCH(COOH)CH2CO2(CH2)2C(O)xe2x80x94N(CH3)2; xe2x80x94NHCH(COOH)CH2CO2(CH2)3-morpholin-4-yl; xe2x80x94NHCH(COOH)CH2CO2(CH2)2OC(O)C(CH3)3, xe2x80x94NHCH(CH2COOH)CO2(CH2)3xe2x80x94N+(CH3)3; xe2x80x94NHCH(CH2COOH)CO2(CH2)2C(O)N(CH3)2; xe2x80x94NHCH(CH2COOH)CO2(CH2)3-morpholin-4-yl; xe2x80x94NHCH(CH2COOH)CO2(CH2)2OC(O)C(CH3)3, xe2x80x94NHCH(COOH)CH2CO2CH3; xe2x80x94NHCH(CH2COOH)CO2(CH2)2N(CH3)2; xe2x80x94NHCH(COOH)CH2CO2CH2C(O)N(CH3)2; xe2x80x94NHCH(CH2COOH)CO2CH2C(O)N(CH3)2; xe2x80x94NHCH(CH2COOH)CO2CH3; xe2x80x94NH(CH2)3N(CH3)2; xe2x80x94NHCH2CH2CO2CH3; xe2x80x94NHCH[CH2CO2CH2C(O)N(CH3)2]xe2x80x94CO2CH2xe2x80x94C(O)xe2x80x94N(CH3)2; xe2x80x94NHCH2CO2CH3; -N-(methyl 3-amino-3-deoxyaminopyranoside); -N-(methyl 3-amino-2,3,6-trideoxyhexopyranoside); xe2x80x94N-(2-amino-2-deoxy-6-(dihydrogenphosphate)-glucopyranose; -N-(2-amino-2-deoxygluconic acid); xe2x80x94NH(CH2)4COOH; xe2x80x94Nxe2x80x94(Nxe2x80x94CH3-D-glucamine; xe2x80x94NH(CH2)6COOH; xe2x80x94O(D-glucose); xe2x80x94NH(CH2)3OC(O)CH(NH2)CH3; xe2x80x94NH(CH2)4CH(C(O)-2-HOOC-pyrrolidin-1-yl)NHCH(COOH)-CH2CH2Ph (S,S isomer); xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)9CH3; xe2x80x94NH(CH2)C(O)CH2C(O)N(CH3)2;
Preferably, R4, R6 and R7 are each independently selected from hydrogen or xe2x80x94C(O)Rd. More preferably, R4, R6 and R7 are each hydrogen.
Preferably R5 is hydrogen, xe2x80x94CH2xe2x80x94NHRc, xe2x80x94CH2xe2x80x94NRcRe or xe2x80x94CH2xe2x80x94NHxe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x. R5 can also preferably be hydrogen; xe2x80x94CH2xe2x80x94Nxe2x80x94(Nxe2x80x94CH3-D-glucamine); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)9CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHC(O)xe2x80x94(CH2)3COOH; xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)9CH3;-CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94COOH; xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)5COOH; xe2x80x94CH2-(morpholin-4-yl); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2CH2OH; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH(OH)xe2x80x94CH2OH; xe2x80x94CH2xe2x80x94N[CH2CH2O H]2; xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)3xe2x80x94N(CH3)2; xe2x80x94CH2xe2x80x94N[(CH2)3xe2x80x94N(CH3)2]2; xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)3-(imidazol-1-yl); xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)3-(morpholin-4-yl); xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)4xe2x80x94NHC(NH)NH2; xe2x80x94CH2-N-(2-amino-2-deoxygluconic acid);xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)11CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH(COOH)CH2COOH; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)7CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)8CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)9CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHSO2xe2x80x94(CH2)11CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)7CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2 CH2OH; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2C(O)xe2x80x94N-(D-glucosamine); xe2x80x94CH2xe2x80x94NHxe2x80x94(6-oxo-[1,3]oxazinan-3-yl); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)9CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)11CH3; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)6Ph; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)8Ph; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)10Ph; xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94Sxe2x80x94CH2-(4-(4xe2x80x94CF3xe2x80x94Ph)Ph); xe2x80x94CH2xe2x80x94NHxe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)11CH3; or xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)5xe2x80x94COOH.
Preferably, R8 is xe2x80x94CH2C(O)NH2, xe2x80x94CH2COOH, benzyl, 4-hydroxyphenyl or 3-chloro-4-hydroxyphenyl.
Preferably, R9 is hydrogen or alkyl.
Preferably, R10 is alkyl or substituted alkyl. More preferably, R10 is the side-chain of a naturally occurring amino acid, such as isobutyl.
Preferably, R11 is hydrogen or alkyl.
Preferably, R12 is hydrogen, alkyl, substituted alkyl or xe2x80x94C(O)Rd. R12 can also preferably be hydrogen; xe2x80x94CH2COOH; xe2x80x94CH2xe2x80x94[CH(OH)]5CH2OH; xe2x80x94CH2CH(OH)CH2OH; xe2x80x94CH2CH2NH2; xe2x80x94CH2C(O)OCH2CH3; xe2x80x94CH2-(2-pyridyl); xe2x80x94CH2xe2x80x94[CH(OH)]4COOH; xe2x80x94CH2-(3-carboxyphenyl); (R)xe2x80x94C(O)CH(NH2)(CH2)4NH2; xe2x80x94C(O)Ph; xe2x80x94C(O)CH2NHC(O)CH3; Exe2x80x94CH2CH2xe2x80x94Sxe2x80x94(CH2)3CHxe2x95x90CH(CH2)4CH3; or xe2x80x94C(O)CH3.
Preferably, X1 and X2 are each chloro.
Preferably, X3 is hydrogen.
Preferably, each Y is independently selected from the group consisting of oxygen, sulfur, xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94NRcxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NRcC(O)xe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NRcSO2xe2x80x94, xe2x80x94C(O)NRcxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94SO2NRcxe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94P(O)(ORc)Oxe2x80x94, xe2x80x94P(O)(ORc)NRcxe2x80x94, xe2x80x94OP(O)(ORc)Oxe2x80x94,xe2x80x94OP(O)(ORc)NRcxe2x80x94, xe2x80x94OC(O)Oxe2x80x94, xe2x80x94NRcC(O)Oxe2x80x94, xe2x80x94NRcC(O)NRcxe2x80x94, xe2x80x94OC(O)NRcxe2x80x94, and xe2x80x94NRcSO2NRcxe2x88x92;
Preferably, n is 0 or 1, and more preferably, n is 1.
Preferred compounds of the invention exclude glycopeptide derivatives substituted at the C-terminus with a substituent that comprises more than one carboxy (COOH) group.
Preferred compounds of the invention exclude glycopeptide derivatives substituted at the C-terminus with a substituent that comprises one or more saccharide groups and a carboxy (COOH) group.
Certain glycopeptide derivatives are described in U.S. patent application Ser. No. 09/470,209, filed Dec. 22, 1999. Accordingly, the compounds of the invention may preferably exclude glycopeptides of formula II: 
a) wherein R3 is OH; R5 is hydrogen; R19 is xe2x80x94CH2[CH(OH)]4COOH; and R20 is xe2x80x94CH2CH2xe2x80x94NHxe2x80x94(CH2)9CH3; or
b) wherein R3 is OH; R5 is hydrogen; R19 is hydrogen; and R20 is xe2x80x94CH2CH2xe2x80x94N(C(O)-3,4,5-trihydroxycyclohex-1-en-1-yl)-(CH2)9CH3 (R,S,R isomer);
A preferred compound of the invention is a glycopeptide of formula II: 
wherein:
R19 is hydrogen;
R20 comprises two or more (e.g. 2, 3, 4, 5, or 6) hydroxy groups and is selected from xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, Rf, xe2x80x94C(O)Rf, and xe2x80x94C(O)xe2x80x94Raxe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x; and
Ra, Y, Rb, Z, x, Rf, R3, and R5 have any of the values or preferred values described herein;
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof,
provided the group R3 does not comprise more than one carboxy group; and
provided the group R3 is not a substituent that comprises one or more saccharide groups and a carboxy (COOH) group.
In one preferred embodiment R20 is substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, substituted alkyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, substituted alkynyl-C(O)xe2x80x94, substituted cycloalkyl-C(O)xe2x80x94, substituted cycloalkenyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94, or heterocyclic-C(O)xe2x80x94; wherein R15 comprises two or more hydroxy groups. More preferably, R20 is substituted alkyl, substituted alkenyl, substituted alkynyl, substituted alkyl-C(O)xe2x80x94, substituted alkenyl-C(O)xe2x80x94, substituted alkynyl-C(O)xe2x80x94; wherein R20 comprises two or more hydroxy groups.
In another preferred embodiment R20 is a group of formula xe2x80x94CH2xe2x80x94CH(OH)CH(OH)CH2xe2x80x94Yxe2x80x94Rbxe2x80x94(Z)x, or xe2x80x94CH2xe2x80x94CH(OH)CH(OH)CH2xe2x80x94R17 wherein Y, Rb, Z and x have any of the values or preferred values described herein, and R17 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic.
The invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention. In one preferred embodiment, the pharmaceutically acceptable carrier comprises an aqueous cyclodextrin solution. Preferably, the cyclodextrin is hydroxypropyl-xcex2-cyclodextrin or sulfobutyl ether xcex2-cyclodextrin. More preferably, the cyclodextrin is hydroxypropyl-xcex2-cyclodextrin.
The compounds of the invention are highly effective antibacterial agents. Accordingly, the invention also provides a method of treating a mammal having a bacterial disease, comprising administering to the mammal a therapeutically effective amount of a compound of the invention. The invention also provides a method of treating a mammal having a bacterial disease, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the invention.
The invention also provides processes and intermediates useful for preparing compounds of the invention, which processes and intermediates are described further herein.
The invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a bacterial disease in a mammal.
Preferred compounds of the invention are the compounds of formula II shown in Table I below wherein R19 is hydrogen.
Another preferred group of compounds of the invention are polyhydroxy derivatives of the glycopeptide antibiotic A82846B (also known as chloroorienticin A oy LY264826). See for example R. Nagarajan et al., J Org Chem., 1988, 54, 983-986; and N. Tsuji et al., J. Antibiot., 1988, 41, 819-822. The structure of this glycopeptide is similar to vancomycin, except A82846B contains an additional amino sugar (i.e. 4-epi-vancosamine attached at the R2 position in formula I.) and further contains 4-epi-vancosamine in place of vancosamine in the disaccharide moiety attached at the R1 position in formula I. For example, a preferred group of compounds are derivatives of A82846B that are substituted at the 4-epi-vancosamine nitrogen with a substituent that comprises two or more (e.g. 2, 3, 4, 5, or 6) hydroxy groups; or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. Another preferred group of compounds of the invention are derivatives of A82846B wherein the 4-epi-vancosamine has been replaced with a group selected from the values defined herein for R1 in a compound of formula I. The compounds of the invention that are polyhydroxy derivatives of A82846B can readily be prepared using the procedures described herein.
The polyhydroxy glycopeptide derivatives of the invention have been found to unexpectedly exhibit reduced tissue accumulation and/or nephrotoxicity when administered to a mammal. While not wishing to be bound by theory, it is believed that the hydroxy groups serve to increase the overall polarity of the glycopeptide under physiological conditions thereby facilitating excretion from the mammal after administration. The unexpected increase in excretion of the polyhydroxy compounds of the invention may be responsible for the reduced tissue accumulation and/or reduced nephrotoxicity observed for these compounds relative to the corresponding compounds that lack the hydroxy groups functionality.